Summary: Facial clefts are one of the most common birth defects, affecting 2 out of every thousand babies. While the main causes of facial clefts are unknown, it is obvious that genetics plays a strong role. We've shown that families with one member affected by clefts are 40 times as likely to have a baby with a cleft. Environmental factors are also presumed to play a role in clefts. For example, clefts are easily produced in experimental animals exposed to teratogens. It is likely that humans vary in their genetic susceptibility to teratogens that cause clefts. More than a decade ago, we anticipated that genetic susceptibility would become an important area of epidemiologic research at NIEHS. Accordingly, we selected facial clefts as a condition with both genetic and environmental causes, and we began in 1992 to develop a study to address the causes of clefts. In 1996 we launched a population-based case-control study of facial clefts in Norway. (Norway has one of the highest rates of cleft lip and palate in the world.) The field phase was completed in 2002. We enrolled 88% of all babies with facial clefts born in Norway between 1996 and 2002 (574 cases), and 76% of eligible control infants (763) selected randomly from the population. Mothers of these infants provided detailed information on occupational and other exposures during pregnancy, as well as on nutrition, personal habits and medical history. Biological samples for DNA analysis were collected from cases and controls as well as their mothers, fathers and siblings. These total nearly 4000 people. DNA has been extracted from these samples and is now ready for genetic analysis. In the course of carrying out this study, we developed and published a new statistical strategy for the analysis of genetic data in case-parent triads that has been widely adapted. We have demonstrated the application of this new method in a preliminary analysis of 262 case-parent triads. We are working intensively on analyses of folic acid, cigarette smoking and hazardous occupations, and their effects on the risk of facial clefts. In our most recent analyses we have demonstrated a dose-response association between high levels of maternal alcohol consumption and the risk of facial clefts. In order to pursue a more biologically based understanding of this association, we have compared this risk among subgroups of mothers and offspring who are carrying a susceptibility allele of the ADH-1C gene, which plays a key role in the metabolism of alcohol to acetaldehyde. We found no evidence of increased risk among mothers and offspring who did not carry the at-risk allele, and high risk among those who did carry the allele. This suggests that the capacity to metabolize alcohol may play an important role in the teratogenic effect of alcohol. This information may be useful in the identification of other toxic effects of alcohol on human reproduction. In collaboration with an international consortium of clefts researchers, we have contributed data to a GWAS analysis to explore specific common genetic variants that may play a role in the high familial risk of facial clefts. This GWAS analysis has confirmed the importance of IRF6 as an important risk factor for facial clefts, and identified MAFB and ABCA4 as novel candidate genes.